MELOXICAM

1. Pharmacokineticsofmeloxicam;
Aims The aim of the present study was to determine how the
pharmacokinetics of meloxicam are affected by kidney dysfunction and
consequently to define the appropriate dose for the use of meloxicam
in patients with mild or moderate renal impairment.
Methods Meloxicam was administered to subjects with mild (creatinine
clearance 41–60 ml min−1) to moderate (20–40 ml min−1) renal
impairment compared with normal renal function (>60 ml min−1
).
Thirty-eight subjects received meloxicam 15 mg once daily over 9 days.
Meloxicam plasma concentrations were determined from blood
samples taken during the study and pharmacokinetic parameters
calculated according to noncompartmental methods.
Results Subjects with no or mild renal impairment showed sinular
pharmacokinetic profiles (geometric mean AUCSS (%gCV) 55 (33%) vs 55
(38%) μg ml−1
h). Subjects with moderate renal impairment
demonstrated lower total plasma meloxicam concentrations (AUCSS 35
(50%) μg ml−1
h, with corresponding higher plasma clearance (P= 0.013)
compared with subjects with no renal impairment. However, this was
combined with higher meloxicam free fractions in moderately impaired
subjects such that free meloxicam concentrations were similar in all
three groups. Meloxicam was well tolerated with few adverse events
occurring and no difference in incidence observable between groups.
Conclusions On the basis of these results there is no necessity for a
dosage adjustment when administering meloxicam to patients with
mild to moderate renal impairment.
Meloxicam [4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H- 1,2-
benzothiazine-3-carboxamide-1,1-dioxide] is a new nonsteroidal
antiinflammatory drug belonging to the enolic acid group. In a

2. crossover study, 30 mg 14C-labeled meloxicam was administered to
four male healthy volunteers as a short-term infusion and as an oral
solution. The objectives of the study were to determine the mode of
elimination, the excretion balance, the in vivo binding characteristics to
serum proteins, and to investigate the metabolic pattern in plasma,
urine, and feces. A comparison of plasma concentration measurements
of unchanged drug by a specific HPLC assay and total radioactivity by
liquid scintillation counting revealed a very close conformity. Over 90%
of the plasma radioactivity was represented by unchanged drug. Its
terminal and dominant half-life of elimination from plasma, as
determined from plasma and urinary data in this study, ranged from 12
to 17 hr in the volunteers. The serum protein binding of the
radioactivity from in vivo samples was very high (99.1-99.7%). The
excretion balance was complete after 6 days. Average urinary excretion
of 14C-radioactivity accounted for 43% of the dose, with the remainder
appearing with the feces. Meloxicam was extensively metabolized, with
only traces of the drug appearing unchanged in urine and feces. The
main metabolites were formed by hydroxylation and further oxidation
of the methyl group of the thiazolyl moiety. In addition, two further
metabolites were found, particularly in urine. Altogether, > 95% of the
dose excreted could be accounted for by the metabolites identified or
the parent compound itself. The pharmacokinetic profile of the new
nonsteroidal anti-inflammatory drug meloxicam was investigated in a
number of animal species, including mice, rats, dogs, mini-pigs, and
baboons, after administration of [14
C]meloxicam. The plasma
concentration-time profiles for meloxicam in rats and dogs were
comparable to that in humans, whereas there were marked differences
between humans and mice, mini-pigs, and baboons. The highest tissue

3. concentrations of meloxicam in rats and mini-pigs were seen in the liver
and kidneys. In contrast, low concentrations of meloxicam were found
in the central nervous system, compared with those in plasma. The
excretion balance in mini-pigs resembled that in humans, with almost
equal concentrations being eliminated in the urine and the feces. As in
humans, meloxicam circulated mainly in the form of the parent
compound in the plasma of mice, rats, dogs, mini-pigs, and baboons.
The main metabolites in rats, mini-pigs, and humans were a 5′-
hydroxymethyl derivative (AF-UH 1 SE) and a 5′-carboxy metabolite
(UH-AC 110 SE). The percentage of meloxicam binding to protein was
higher in rats and humans (>99%) than in other species. The
pharmacokinetic profile of meloxicam in rats most closely resembles
that in humans; therefore, reliable clinical predictions can be made
from studies in this rodent species.
Meloxicam [4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-
benzothiazine-3-carboxamide-1,1-dioxide] is a nonsteroidal anti-
inflammatory drug (NSAID) of the oxicam class which shows
preferential inhibition of cyclo-oxygenase-2.
Meloxicam has a plasma half-life of approximately 20 hours, making it
convenient for once-daily administration. Meloxicam is eliminated after
biotransformation to 4 pharmacologically inactive metabolites, which
are excreted in urine and faeces. Meloxicam and its metabolites bind
extensively to plasma albumin. Substantial concentrations of
meloxicam are attained in synovial fluid, the proposed site of action in
chronic inflammatory arthropathies.

4. Neither moderate renal nor hepatic insufficiency significantly alter the
pharmacokinetics of meloxicam. Dosage adjustment is not required in
the elderly. Drug-drug interaction studies are available for some
commonly co-prescribed medications. Concentration-dependent
therapeutic and toxicological effects have yet to be extensively
elucidated for this NSAID. The synovial mean transit time of diclofenac
was determined by two methods from existing plasma and synovial
fluid concentration-time data. These data were obtained from single-
and multiple-dosing regimens of diclofenac in patients with
osteoarthritis and rheumatoid arthritis. Plasma and synovial fluid
concentration-time data taken from the literature for four other
nonsteroidal antiinflammatory drugs (etodolac, ibuprofen,
indomethacin, and tenoxicam) were also analyzed. The two methods of
data analysis rely on the determination of the ratio of the area under
the synovial fluid concentration-time curve to the area under the
plasma concentration-time curve. Both methods can be considered
noncompartmental because in determining the first-order exit rate
constant for the synovial fluid (the inverse of the synovial mean transit
time), an analysis of the overall distribution and elimination
characteristics of the drug is unnecessary. Method 1 makes use of the
information contained in the postdistributional synovial fluid to plasma
concentration ratio whereas method 2 is a linear pharmacokinetic
model using a partial-areas analysis. The single dose mean ± S.D.
synovial fluid exit rate constant for diclofenac was 0.39 ± 0.33 hr^−1 (n
= 6), which was not significantly different from that determined by
method 2; which was 0.49 ± 0.52 hr^−1. The steady state mean ± S.D.
diclofenac synovial fluid exit rate constants for methods 1 and 2 were
0.43 ± 0.18 and 0.54 ± 0.71 hr^−1 (n = 8), respectively, which were not

5. significantly different. These values of synovial fluid exit rate constants
result in a synovial mean transit time for diclofenac that is
approximately 2 to 2.5 hours. The synovial mean transit time calculated
using method 1 from literature data for etodolac, ibuprofen,
indomethacin, and tenoxicam were 6.8, 2.2, 4.8, and 3.5 hours,
respectively. The synovial mean transit times calculated by method 2
for the same drugs were 5.3, 3.4, 4.7, and 4.0 hours, respectively.
Similar values of the synovial mean transit time of nonsteroidal
antiinflammatory drugs were achieved by using either of these two
methods, both of which avoid complex equation fitting which is
statistically problematic in the frequently data-sparse environment of
extravascular sampling.